Growth is fundamental to animal development, yet surprisingly little is known about the mechanisms that control organ size. Secreted signaling molecules of the bone morphogenic proteins (BMP) and other families are key regulators of pattern formation as well as cell proliferation in many organs. However, how these signaling pathways induce organ growth and why organs stop growing at their appropriate size is not known. Our long-term objectives are to understand the molecular mechanisms that control organ growth. We are using the Drosophila wing and eye imaginal discs as genetic model systems to accomplish this goal and to study genes that control organ size. Over the last granting period, we discovered a novel growth control pathway, the Hippo signaling pathway. Several components of the Hippo pathway have been identified and a signal transduction pathway from the plasma membrane into the nucleus has emerged. Hippo signaling is required for cells to stop proliferation when organs have reached their proper size and hippo mutant animals produce severely overgrown structures. The Hippo pathway is thus a key regulator of organ growth. However, several important questions have not yet been addressed: How is the Hippo pathway regulated and what is its role during normal growth and during regeneration? How does the Hippo pathway interact with other pathways that regulate organ growth such as secreted signaling molecules? In the current proposal, we will study how the Hippo pathway interacts with the Dpp and EGFR/Ras signaling pathways which serve as paradigms to determine how patterning is linked to growth control. We will further analyze the regulation and function of the Hippo pathway in tissue regeneration and identify missing components of the Hippo pathway. Our Specific Aims are (1) to determine the regulation and function of the Hippo pathway in tissue regeneration, (2) to characterize the interaction between the Hippo and the Drosophila BMP homolog Dpp pathways, (3) to elucidate the interaction between the EGFR and the Hippo pathways, and (4) to identify additional components of the Hippo pathway. Our studies will reveal novel information of how cells interact with each other to control cell proliferation and organ size. The Hippo pathway is highly conserved in humans where several components of the Hippo pathway are directly involved in the development of cancer. A deeper understanding of the Hippo pathway and the identification of the molecular machinery that interacts with Hippo signaling in Drosophila should therefore reveal significant new insights into the mechanisms of normal development as well as cancer in humans. Public Health Relevance: This research project employs a model genetic organism, the fruit fly, to uncover the genetic control of organ growth and cell proliferation, a process of immediate relevance to human health. Growth is critical for normal development and growth control is defective in cancer cells. Given the conservation of genes required for most fundamental biological processes we expect that this project will inform our understanding of growth control and cell proliferation in vertebrates and in pathophysiological states, such as cancer.